The overall goal of our research program is to identify and understand the mechanisms of action of specific[unreadable] genes that modulate risk for cancer development in inbred mice. These studies will provide insights into the[unreadable] signaling pathways critical for hepatocarcinogenesis in mice, as well as models for understanding the action[unreadable] of modifier genes for cancer risk in humans. We have identified the Hcs7 locus as the major determinant of[unreadable] the high susceptibility of C3H/HeJ (C3H) and CBA/J mice to liver tumor induction relative to C57BL/6J (B6)[unreadable] mice and demonstrated that this gene is located on distal Chromosome 1. We also found that one of the[unreadable] susceptibility genes, Hcf2, carried by sensitive C57BR/cdJ (BR) mice mapped to the same region.[unreadable] Comparative studies of hepatocarcinogenesis in C3H, BR, and B6 mice by our group and others[unreadable] demonstrate that the Hcs7 and Hcf2 loci act cell autonomously to control the growth or development of[unreadable] preneoplastic hepatic lesions, but the molecular identities of these genes are still unknown. We have[unreadable] localized the Hcs7gene to a 6.4 Mbp interval on Chromosome 1. We propose to elucidate the mechanisms[unreadable] by which Hcs7 modulates liver cancer risk through the following approaches. First, we will determine the[unreadable] molecular identity of Hcs7 through positional cloning. We will prioritize candidate genes based on mapping[unreadable] to sub-centiMorgan resolution, analysis of shared SIMP haplotypes for relevant strains, hepatic gene[unreadable] expression, and functional criteria. Candidates will then be tested by transgenesis using Bacterial Artificial[unreadable] Chromosome (BAG) clones or gene replacement. Second, we will elucidate the biological basis for Hcs7[unreadable] modulation of cancer risk by comparing Hcs7 BAG transgenic or allelic replacement strains to control[unreadable] parental or congenic mice for phenotypes related to hepatocarcinogenesis. Finally, we will determine the[unreadable] molecular mechanisms by which Hcs7 acts through analysis of hepatic gene expression in BAG transgenic[unreadable] and congenic mice, and characterization of mice carrying germ-line or liver-specific null mutations in Hcs7.